CN106421889A - Regenerative medical material and preparation method and application thereof - Google Patents
Regenerative medical material and preparation method and application thereof Download PDFInfo
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
- A61K8/345—Alcohols containing more than one hydroxy group
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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Abstract
The invention provides a regenerative medical material for promoting soft or hard tissue repair and a preparation method and application thereof. The regenerative medical material has a three-dimensional network structure and is a composite material prepared from inorganic matter and organic matter, wherein the mass ratio of the inorganic matter to the organic matter is 2:1 to 4:1. Based on the total mass of the inorganic matter, the inorganic matter contains 12-38% of SiO2, 3-5% of Na2O, 15-29% of CaO, 10-32.5% of P2O5, 1-5% of inositol hexaphosphate, 1-5% of inositol hexaphosphoric acidand the balance impurities, and the content of the impurities is 0.5% or below. Based on the total mass of the organic matter, the organic matter contains 30-60% of carboxymethyl chitosan and 30-60% of sodium hyaluronate. The regenerative medical material has the composition and the properties suitable a human body and has the key effect on the aspects of cell repair and bonding, cell proliferation and promotion of hair follicle growth.
Description
Technical field
The present invention relates to regenerative medicine field, more particularly to a kind of regenerative medicine material and its preparation method and application.
Background technology
After bioactivity glass and the most significant feature of glass ceramics are implantation human body, surface appearance becomes in time and dynamically
Change, surface forms carbonated hydroxyapatite (HCA) layer of biologically active, provide bonded interface for tissue.Most biologically actives
Glass is A class bioactive materials, existing ostosis (osteoproductive), has bone guided again
(osteoconductive) act on, have good associativity with bone and soft tissue, bioactivity glass (BAG) is considered as
Can be applicable to the good biological material in reparation field.The purposes of this kind of prosthetic material is not only extremely wide, and in numerous necks
Irreplaceable mystery effect had on the professional product in domain, such as skin nursing, whitening go wrinkle, empyrosis, canker sore,
Intestine gastric ulcer, exanthemv, killing fungi, bonding of bone repair, soft tissue and bone tissue etc., its appearance will be good for for the mankind
Health makes outstanding contribution.Additionally, BAG also has the reaction of quick surface；Amorphous two-dimensional structure makes intensity and fracture toughness low；
Elastic modelling quantity (30-35MPa) is low, close with cortex bone；Machinable bio-vitric has good processing characteristics.
But there are some key issues in this bio-vitric：1st, degradation speed is slow, degradable typically requires 1-2
Time；2nd, pH value is unstable, and its pH value can reach 11, forms strong basicity, has certain cytotoxicity；3rd, this bio-vitric
Very high using melt quenching reaction temperature, at 1700-1900 DEG C, cause high energy consumption, building a standard production line needs to invest
More than 1000000000 yuan；4th, this bio-vitric can not form porous material and highly meet and expanding function it is difficult to realize material.
Therefore, it is badly in need of in the market replacing the New Regenerated medical material of above-mentioned bio-vitric.
Content of the invention
In order to solve above-mentioned technical problem, an aspect of of the present present invention, provide a kind of regeneration promoting hard and soft tissue to repair doctor
Learn material, described regenerative medicine material has three-dimensional net structure, and is the composite being made up of inorganic matter and organic matter, its
In, described inorganic matter is 2 with the mass ratio of described organic matter:1-4:1；
Based on the gross mass of described inorganic matter, described inorganic matter comprises 12-38%SiO2, 3-5%Na2O, 15-29%CaO,
10-32.5%P2O5, 1-5% inositol hexaphosphate, 1-5% inositol phosphate, balance of impurity, its content is less than
0.5%；
Based on the gross mass of described organic matter, described organic matter comprises 30-60% carboxymethyl chitosan and 30-60% is transparent
Matter acid sodium.
In preferred embodiments, described inorganic matter and the mass ratio of described organic matter are 3:1.In addition, it is described inorganic
Calcium phosphorus weight ratio in thing is 1.5 to 1.8, preferably 1.67.
In preferred embodiments, described inorganic matter by sol-gel process using soybean skin extract as phosphorus forerunner
Body, at 300～700 DEG C, Isothermal sinter obtains.
Another aspect of the present invention, provides a kind of cellular growth support, and it comprises above-mentioned promotion hard and soft tissue and repairs
Raw medical material.Preferably, described cellular growth support is medical treatment device, particularly at least a portion of implant.
Another aspect of the invention, provides a kind of method promoting hard and soft tissue to repair, wherein using heretofore described
Regenerative medicine material.
Other aspects of the present invention, provide the regenerative medicine material promoting hard and soft tissue to repair of the present invention in preparation
Purposes in medical composition, medical treatment device, oral care product, plastic surgery articles for use or cosmetics.
The regenerative medicine material of the present invention can better control over the degradation speed of material, so that protozoa activity glass is degraded fast
Degree is controlled, makes in artificial bone application the degradation speed of newborn bone implant material synchronous, overcomes area of new bone to be unable to reach
Bone structure, form, the phenomenon of triple reparations of function.When be used in Bone Defect Repari, backbone and Cranial defect, oral cavity bone implantation etc. aspect
When, the regenerative medicine material tool of the present invention has very great significance.
In the present invention, phosphorus is introduced by soybean extract, can improve the degradation speed of regenerative medicine material, traditional system
The compositional range of the biologically active of material of Preparation Method preparation is less, to limit degradation speed typically by the content reducing phosphorus.
The material of former conventional method preparation generally uses phosphoric acid, etherophosphoric acid etc., its compatibility with the presoma (such as calcium nitrate) of calcium
Poor, easily cause precipitation to occur to separate.Select the larger ethylene glycol of toxicity, reduce the concentration of presoma, so process solvent
During can expend the substantial amounts of energy and time, and standardization difficult to realize, large-scale production.
The phosphorus presoma of the present invention can be effectively altogether molten with calcium presomas such as such as calcium nitrate, solvent is water, ethanol or
Its mixture, toxicity is less, and solvent removal temperature is relatively low, by changing the presomas such as calcium, sodium, realizes being formed under room temperature situation and coagulates
Glue, realizes reaching every physical and chemical index of bioactivity glass in 600 DEG C.The shortcoming overcoming conventional method, realization standardization,
Large-scale production.
In the regenerative medicine material of the present invention, 1% to 10% silicon atom has more than 5 high ligancy, and these
High coordination silicon is formed at ambient pressure.High coordination silicon all has a certain impact to the structure of material and performance, and such as high coordination silicon can make
Ultraviolet radiation absorption peak shifts.
In solution synthesis, most of at present high coordination silicon are main and N, F or CI are coordinated, few and O coordination.By changing
Environmental stimuli, such as temperature, solvent and irradiation intensity can change the ligancy of silicon atom, and rising high-temperature can make the silicon of 5 coordinations increase
Plus, can mutually change between 5 coordination silicon and 6 coordination silicon under irradiation.If introducing polyalcohol, be conducive to improving high coordination
The formation probability of silicon, polyalcohol can promote O to be coordinated with silicon atom, thus forming high coordination silicon.In high coordination silicon, usually in glass
The high-temperature process of glass material, can make silicon ligancy be changed into 6 by 4, mainly presented in Si-O-P or Si-O-Si, with P
Content increase, 6 coordination silicon increase, and through Overheating Treatment, glass material can crystallize, and it is former to contain high coordination silicon under middle low temperature, normal pressure
Research also the solid material of the silicon of son does not occur at present.
The regenerative medicine material of the present invention is better than physical and chemical index and the Biological indicators of bioactivity glass.This material is producing
When, achieve in 600 DEG C of low-temperature energy-savings, quality controllable large-scale production, changes former 1700-1900 DEG C of calcining high energy consumption, low yield
The shortcomings of product qualification rate.In the case of with this regenerative medicine material as parent, add other medical materials, will be widely applied
In biological therapy field.
It is preferable that calcium-phosphorus ratio is relatively uniform with skeleton in the regenerative medicine material of the present invention, for example, 1.67 is left
Right.Formed tridimensional network and aperture can realize consistent with skeleton and soft tissue aperture.Realize the biology of material
Activity, stability and degradation speed are controlled.This material preparation temperature is low, can be loaded into bioactive molecule, such as protein, anti-
Rhzomorph, chemotherapeutics, and there is porous, can be used for drug loading and controlled release, the phosphorus presoma simultaneously selected is natural
Material, minimum with traditional phosphorus presoma relative toxicity, thus improving the biocompatibility of material.Material is in simulation human body fluid
(SBF), in, quickly form hydroxyapatite on surface.This material can overcome the poor plasticity of traditional biological activity glass.Shape
Become adjustable amorphous materials, non-crystal structure.Other biological activity glass is essentially crystalline solid, the regenerative medicine material of the present invention
Expect for noncrystal, the particle of material uniformly, the biocompatibility of material stable, preferably, stability is strong for dispersiveness.In artificial bone
In to realize compressive strength, degradation speed all controlled.
The regenerative medicine material of the present invention contains Si, Ca, Na, P ion, the ratio of each ion and the ion of body bone tissue
Unanimously.The SiO being distributed in high-temperature calcination of these uniform ions2Multiple aperture in, naturally make material and body fluid occur eight
The reaction of step surface.
The first step：Na in material+And K+Uniform ion is distributed in the SiO of multiple aperture2In (its aperture and skeleton hole
Footpath is almost consistent), they run into body fluid, and H+And H3O+Ion exchanges rapidly, such as：
Si-O-Na++OH-→Si-OH++Na++OH-
Wherein OH-For negative electrical charge, adsorb the material such as bone tissue and soft tissue cells, growth factor, collagen toward aperture
Middle ordering growth, forms organization of human body growth machine block.Allow regenerative cell's gene expression, ordering growth, form bone guided, osteoacusis
Ability.
Second step：Si-O-Si key, is interrupted by solution, forms many Si-OH outside interface；
3rd step：The polymerisation of Si-OH can form SiO2Porous limbs layer；It is led to different types of protein
Cross hydrogen bond and ion amine key (- Si-O-H3N+-) combine to form highdensity protein adsorption, form silica sol layer and carbonic acid hydroxyl phosphorus
Grey rock layers, and this grey rock layers has high surface, is suitable for adsorbing substantial amounts of biomolecule, thus promoting extracellular to respond.Compare
In the silica sol layer with relatively low negative charge amount, area of new bone adsorbs more biomolecule.
4th step：High coordination silicon atom 6, silicon atom 4 and human body potassium ion exchange, and form stable three-dimensional netted solid state machine
Structure, the former silicon atom of change is free state.Can naturally exchange with anthropochemistry composition, form the carrier of creeping substitution, high coordination
Silicon can make ultraviolet radiation absorption peak shift, and plays oxidation resistant effect.
Si-OH+OH-Si→Si-O-Si-+H2O；
5th step：Ca2+And PO4 3-In source material or in source and solution, in rich SiO2Assemble on limbs layer and form CaO-
P2O5Unformed phase layer；By the ratio of P, to regulate and control neonatal cell and the degraded of former implant is synchronous.
6th step：With OH- and CO3 2-Draw from solution, CaO-P2O5Omnidirectional phase layer will convert to the hydroxyl of carbon containing
Lime stone (HCA) polycrystal, absorption, in wound, ulcer and soft tissue surfaces, reaches promotion cel l proliferation, promotes wound healing
Conjunction, the seamless reparation of wound.
7th step：Promote cell proliferation ordering growth, promote the formation of hair follicle, promote the growth of hair follicle, reach minimizing scar
The effect of trace.
8th step：Ulcer wound surface, particularly canker sore, cervical erosion is all that anaerobic bacteria causes, the regeneration doctor of the present invention
Learn material and can form mild alkaline conditions, allow anaerobic bacteria to be dehydrated and dead, the growth of suppression anaerobic bacteria simultaneously, promote repairing of neonatal cell
Multiple, propagation.
In sum, the regenerative medicine material of the present invention not only has the various properties being suitable for human body, but also has
The composition more consistent with human body and relation with contents, thus be more suitable for tissue repair.
Brief description
Fig. 1 be exemplary regenerative medical material of the present invention X-ray fluorescence spectra (XRF) Elemental redistribution picture (210 ×
210μm2).It is homogeneous that it shows that material of the present invention chemical composition (Ca, P and Si) on a microscopic scale is distributed.
Fig. 2 is the XRD spectra of exemplary regenerative medical material of the present invention and SBF solution reaction different time.
Fig. 3 is the SEM-EDXS figure of the exemplary regenerative medical material of the present invention.Before a- deposition, after b-SBF deposition
(14d).
Fig. 4 is the exemplary regenerative medical material of the present invention and its MTT value of leaching liquor and Gegenbaur's cell interaction.
A () regenerative medicine material directly cultivates 1d, 6d；The leaching liquor culture 24h of (b) Regesi regenerative medicine material different time.
Fig. 5 cultivates the SEM figure of different time for cell (MC3T3) before skeletonization on bio-vitric piece.
Fig. 6 be the present invention exemplary regenerative medical material piece in SBF solution pH value change.
Fig. 7 is the weight change in water for the exemplary regenerative medical material of the present invention.
Fig. 8 is result figure when backbone and segmental defects are repaired for the Regesi regenerative medicine materials application.
Fig. 9 is with Regesi regenerative medicine material as core, the ulcer of the research and development therapeutic effect of repair materials (gel)
Figure.
Figure 10 is easy to the lab diagram applying for Regesi regenerative medicine material.The regenerative medicine material of its explanation present invention can
Melt film forming under shell temperature.
The lab diagram that Figure 11 affects for wound healing for regenerative medicine material.The regenerative medicine material of its explanation present invention
Improve speed and the quality of wound healing, hairiness Tibetan household slave becomes.
Figure 12 be regenerative medicine material as compound cancellous bone filling porous support when, Cranial defect position regeneration figure.Its
Illustrate and cancellous bone similar mechanical, the material of the present invention promotes the regeneration of defect bone.
Figure 13 be the present invention regenerative medicine material with as comparison 45S material compared with when, for generate bone property
The comparison of energy.The too fast easy formation bone of its explanation 45S degradation speed collapses, and hardness is too strong easily to cause periphery to fracture.
Figure 14 is the impact to Hacat cell proliferation for the 45S leaching liquor.
Figure 15 is the figure of the degradation experiment of 45S powder.
Specific embodiment
Now describe the various exemplary embodiment of the present invention in detail, this detailed description is not considered as the limit to the present invention
System, and it is understood as the more detailed description to certain aspects of the invention, characteristic and embodiment.
It should be understood that heretofore described term is only to be to describe special embodiment, it is not intended to limit this
Bright.In addition, for the number range in the present invention it is thus understood that it is also specifically disclosed that this scope upper and lower bound between every
Individual median.In in the median in any statement value or stated ranges and any other statement value or in described scope
Between each less scope between value be also included in the present invention.These small range of upper and lower bounds can independently include
Or exclusion in the range of.
Unless otherwise stated, all technology used herein and scientific terminology have the routine in field of the present invention
The identical meanings that technical staff is generally understood that.Although the present invention only describes preferred material and application, the present invention's
Can also use and similar or equivalent any material described herein in implementing or testing.The all documents mentioned in this specification
It is incorporated by reference into, in order to the disclosure and description method related to described document and/or material.Rushing with any document being incorporated to
When prominent, it is defined by the content of this specification.
In the present invention, vocabulary of terms had both included singulative, also included plural form, unless context separately clearly refers to
Go out.Heretofore described " at least one " or " at least one " refer not only to the situation that comprises " one " or " a kind of ", heavier
The situation also comprising " multiple " or " multiple " wanted.
Term " regenerative medicine material " of the present invention refers to there is the three-dimensional grid promoting hard and soft tissue regeneration function
The inorganic-organic composite material of structure, also referred to Regesi regenerative medicine material sometimes, or Regesi etc., these titles are at this
There is in invention identical implication.Preferably, inorganic matter described in regenerative medicine material and the mass ratio of described organic matter are 2:
1-4:1.If this mass ratio is less than 2:1, then the hardness of gained regenerative medicine material be deteriorated it is impossible to well as cell growth
Carrier.On the other hand, if this mass ratio is more than 4:1, then the content of each element and tissue in inorganic matter, particularly firmly
In tissue such as bone, the content difference of each element is larger, thus being unfavorable for tissue, the particularly regeneration of sclerous tissues.Preferably,
Inorganic matter is 2.5 with the mass ratio of organic matter:1-3.8:1, more preferably 2.6:1-3.5:1, further preferred 2.8:1 to 3.4:1,
For example, 3:1 etc..
In the present invention, based on the gross mass of inorganic matter, the SiO in inorganic matter2Content is 12-38%, preferably 15-35%,
More preferably 16-33%, further preferred 18-30%, for example, 20%, 25%, 28%, 29% etc..Na in inorganic matter2The content of O
For 3-5%, preferably 3.5-4.5%, more preferably 3.6-4.2%, further preferred 4%.In inorganic matter, the content of CaO is 15-
29%, preferably 16-27%, more preferably 18-25%, more preferably 20-22%.P in inorganic matter2O5Content be 10-
32.5%, preferably 12-30%, more preferably 14-28%, further preferred 16-26%, further preferably 18-24%, 20-22%.This
In invention, the content of inositol hexaphosphate is 1-5%, preferably 2-4%, more preferably 3%.Inositol phosphate in the present invention
Content is 1-5%, preferably 2-4%, more preferably 3%.If the content of above-mentioned each composition is too low or too high in inorganic matter, regenerate
The content of each element and body in medical material, such as in human body, the constituent content of sclerous tissues's such as bone will not be consistent, thus
It is unfavorable for promotion organization regeneration or repair.
In the present invention, can add as single composition as inositol hexaphosphate and inositol phosphate, also can lead to
Cross to be contained in soybean extract and be mixed in preparation process.
In the present invention, be in addition to above-mentioned each composition in inorganic matter in preparation process of the present invention inevitable produce miscellaneous
Matter, as impurity, its content is typically smaller than 0.5 mass %, preferably smaller than 0.4 mass %, more preferably less than 0.2 mass %, spy
Not You Xuan little Yu 0.1 mass %, most preferably 0.
In the present invention, based on the gross mass of organic matter, in organic matter, the content of carboxymethyl chitosan is 30-60%, preferably
40-55%, more preferably 45-50%, further preferred 48%.In organic matter, the content of Sodium Hyaluronate is 30-60%, preferably
40-55%, more preferably 45-50%, further preferred 48%.
It is preferable that the calcium phosphorus weight ratio in described inorganic matter is 1.5 to 1.8, preferably 1.67, in this scope in the present invention
Interior calcium-phosphorus ratio meets the calcium-phosphorus ratio in body such as human body.
It should be noted that in the present invention, in regenerative medicine material, the ratio between the content of institute's composition and each composition is
Content according to each element in sclerous tissues in human body and proportions form.Because of different human body, sex and different age group, hard group
The content knitting middle each element is different, and therefore, in the regenerative medicine material of the present invention, the content of each composition and ratio also have
Institute is different, but these contents and ratio can not exceed the above-mentioned scope referring on the whole.
For example, for the elderly colony, its preferred component content and ratio can be as described below：
Gross mass based on inorganic matter.
Carboxymethyl chitosan 50%；
Sodium Hyaluronate 50%；
Gross mass based on organic matter.
For the elderly colony, preferred calcium phosphorus mass ratio is 1.67.
For young man colony, its preferred component content and than regular meeting adapt to adjustment.
In the preparation method of regenerative medicine material promoting hard and soft tissue to repair of the present invention, need to select specifically to plant
Thing extract, thus realizing Advantageous Effects described in regenerative medicine material of the present invention, for example little to 7.4 low ph value, the releasing of P
Put controlled, plant extraction liquid of the present invention is preferably soybean extract.In certain embodiments, the system of soybean extract
Preparation Method includes soybean skin pulverizing → crushed material acidleach, filters → leach the liquid caustic soda neutralization → calcium precipitation molten → RH of leaching+Resin from
Sub- exchange → evaporation and concentration → soybean extract, wherein in soybean extract, the content of hydroxyl phosphorus needs for 40-60 weight %.
Specifically, the preparation process of the soybean extract of the present invention is as follows：
Take after pulverizing through sieving the soybean skin of about 20 mesh, plus the water of 6 times amount.Use 7% hydrochloric acid, adjust pH to 1.5～2, in room
Temperature stirring dipping.Suction filtration, with 1.2% hydrochloric acid washery slag, waste, merging filtrate.Add lime and be neutralized to pH value about toward in leachate
6.5, obtain the static 1h of calcium precipitation, suction filtration, abandon filtrate use distillation water washing gained sediment 2-3 time again, obtain the calcium salt of purification.Past
Add a small amount of watery hydrochloric acid in gained calcium salt and be tuned into thin pulp shape, add 2/3 times amount H type storng-acid cation exchange resin after a while.Micro-
Stir 0.5h, make that calcium salt is molten to change into soluble salt solutions.Suction filtration, clean, separation, the thick liquid of extract.
By the molten solubility calcium salting liquid upper prop turning gained to ion exchange column, coutroi velocity carries out ion exchange. now,
Mg in solution2+、Ca2+It is switched to RH Deng foreign ion+On resin, H+Ion is exchanged, with the activated carbon of about 1% amount
Decolouring 1-2 time, separates, then destainer is evaporated under reduced pressure concentration, 70-80 DEG C about of temperature control, and to bottle, solution is in thin viscous, obtains final product
The soybean extract of the present invention, the content of its hydroxyl phosphorus needs for 40-60 weight %.
Plant extraction liquid of the present invention can produce the reason obtain specific regeneration medical material of the present invention
It is not to be perfectly clear, but speculate that being possibly due to plant extraction liquid is increased with the compatibility of the presoma (such as calcium nitrate) of calcium
By force, thus not producing precipitation.In addition, plant extraction liquid is natural component, there is no toxicity.Another reason is, soybean is extracted
Other raw materials in the various other elements containing in liquid, with the present invention interact create expected less than effect.Additionally,
In soybean extract, the content composition of each element is similar to the composition of human body each element, is readily available similar to organization
Regenerative medicine material.
In addition, plant extraction liquid has the Multiple components that material can be made to have three-dimensional structure, and between Multiple components
Interact, thus realizing manufacturing the purpose of regenerative medicine material under low temperature.The shortcoming overcoming conventional method, realization standardization,
Large-scale production.
As silicon precursor, calcium precursor in the present invention, the presoma being usually used in the art can be used.In addition, this
Water and/or ethanol can be used as reaction medium in the preparation method of invention.In the present invention, it is configured to by above-mentioned substance
Gel Precursor sol solution needs to sinter at a lower temperature, such as Isothermal sinter at 300-700 DEG C, and described temperature is also
Preferably 400-600 DEG C, such as 500 DEG C equitemperatures.
In the present invention, described " cellular growth support " refers to be suitable for cell, including but not limited to osteocyte, dermal cell
Growth, the matrix of propagation.Preferably, the regenerative medicine material of the present invention itself can be directly as carrier.Alternatively, the present invention
Regenerative medicine material combine with the other materials being usually used in the art/be combined after as carrier.
Embodiment
The preparation method of Regesi regenerative medicine material
According to the content of following compositions, the presoma of corresponding content is configured to gel precursor solution (by four water nitre
Sour calcium changes calcium chloride into or calcium nitrate does not all affect result).
Gross mass based on inorganic matter.
First, the soybean extract 30ml taking the present invention, in the sample bottle of 50ml, then sequentially adds tetraethyl orthosilicate
(TEOS), second alcohol and water (volume ratio is about 1: 1, and addition is can dissolve aforementioned presoma), stir 30min, in stirring
During add Ca (NO3)2·4H2O (or calcium chloride or calcium nitrate), obtains Gel Precursor sol solution.Solidifying by prepare
Glue precursor sol solution is placed at room temperature and (is typically required 2～10 days, depending on the ratio between each presoma until gel
Example), gel is put in 60 DEG C of baking ovens and is aged more than 1 day, then placing into toast 1 week in 120 DEG C of baking ovens makes solvent therein
All volatilize, be cooled to room temperature.In atmosphere the temperature from ambient of tube furnace is warmed up to 300 with the programming rate of 5 DEG C/min
～400 DEG C, by dry gel natural cooling after constant temperature is sintered at least 10 minutes in the tube furnace at 300 DEG C～400 DEG C,
Obtain the mineral powder in Regesi regenerative medicine material.
In proportion carboxymethyl chitosan, Sodium Hyaluronate are mixed with above-mentioned powder composition, be heated to 45 degrees Celsius.Molten
Solution, stirs, obtains mixture.By 100 grams of medical glycerines, it is preheating to 80 degrees Celsius.Afterwards said mixture is incorporated doctor
With in glycerine, stir (medical glycerine and biomaterial mass ratio are 55: 45).Go the removal of impurity, one-tenthization 24 hours, irradiation goes out
Bacterium, obtains final product the Regesi regenerative medicine material of the present invention.
Regesi regenerative medicine material character is studied
1 physicochemical property：
By X-ray fluorescence spectra (XRF), the chemical composition of material is analyzed, research shows：Material is in microcosmic
Chemical composition (Ca, P and Si) on yardstick is distributed homogeneous, as shown in Figure 1.
Regesi regenerative medicine material is immersed in simulated body fluid (SBF) and carries out sedimentation experiment, by X-ray diffraction
(XRD) research finds, when depositing 7 days, hydroxyapatite (HA) diffraction maximum (as shown in Figure 2) substantially in material surface, and
And the diffraction maximum of prolongation HA over time strengthens, illustrative material surface has more hydroxyapatites to be formed.Depositing 14 days
Afterwards, the diffraction maximum change of HA less, illustrates that the HA being formed completely covers material surface.
By ESEM-energy dispersive x-ray power spectrum (SEM-EDXS), the surface topography of material is analyzed, such as schemes
Shown in 3.Result shows, before depositing in SBF solution, material surface is smooth, and it is Si that EDXS energy spectrum analysis proves that it mainly forms,
P and Ca.And after depositing 14 days in SBF solution, spheroidal particle in material surface.Find after spheroidal particle is amplified, these
Particle is made up of the HA of needle-like, finds that Si content reduces by EDXS energy spectrum analysis, Ca, P content (Ca/P～1.65) simultaneously
Increase, further demonstrate the formation of HA.These results are consistent with XRD result above.
2 biological assessments：
2.1. cell toxicity test：
By the directly DMEM/F12 nutrient solution blending with 10% of 1% Regesi regenerative medicine material powder, it is added into
In 96 orifice plates, then by cell before skeletonization (MC3T3) with 1 × 104Individual/mL is inoculated in 96 orifice plates, DMEM/F12 nutrient solution conduct
Control group, CO2After cultivating 1,6 days (d) in incubator respectively, carry out MTT test, add DMSO, concussion after adding MTT, enzyme joins
In 570nm wavelength mensuration absorbance (Absorbance), measurement result such as Fig. 4 (a) is shown for immunization measurement.Result shows
Regesi regenerative medicine material does not have cytotoxicity.When cultivating 1d, the absorbance of material is slightly lower than blank sample (about
It 92%), illustrate that Regesi regenerative medicine material does not have cytotoxicity, when cultivating 6d, the absorbance of material with blank
Sample is identical, and Regesi regenerative medicine material no cytotoxicity is described.
Regesi regenerative medicine material is contained in 10% DMEM/F12 nutrient solution with the ratio immersion of 5mg/ml, extraction is not
With (1,2,3d) centrifuging and taking supernatant after the time, 24 orifice plate leaching liquors, as blank control group, under the conditions of being all stored in 4 DEG C, are incited somebody to action
Before skeletonization, cell (MC3T3) is inoculated in 96 orifice plates with 1 × 104/mL, after culture in CO2 incubator, adds the leaching of different condition
Extract, 24 hours (h) row MTT experiment afterwards, add DMSO, concussion after adding MTT, ELISA measurement is surveyed in 570nm wavelength
Determine absorbance, shown in measurement result such as Fig. 4 (b).Result shows leaching liquor and the sky of Regesi regenerative medicine material different time
The absorbance of white sample is essentially identical, shows that Regesi regenerative medicine material leaching liquor does not still have cytotoxicity.
2.2. cell adhesion test：
Regesi regenerative medicine material is pulverized last, compressing tablet (diameter 13mm, thickness 2mm).Regesi is regenerated
Medical material piece carries out sterilizing, disinfects, and puts in 24 orifice plates, then by cell before skeletonization (MC3T3) with 1 × 104Individual/mL connects
Plant in 24 orifice plates, cultivate 1d and 3d.Then fix 24h with 2.5% glutaraldehyde at 4 DEG C, with PBS 3 times, ethanol ladder
Degree is de- to wash (50%, 75%, 95% and 100%), after spontaneously drying, metal spraying, and carry out SEM observation, as shown in Figure 5.Result table
Bright, Gegenbaur's cell attachment in bio-vitric surface is good, and during culture 1d, cell is elongated, has filopodia to occur.During culture 3d, carefully
Born of the same parents start to extend further, become big, pseudopodium becomes apparent.It is good thin that these prove that Regesi regenerative medicine materials have
Born of the same parents' compatibility, is conducive to cell to adhere in Regesi regenerative medicine material surface.
3. degradation experiment：
Regesi regenerative medicine material piece (PSC, 45S5 and S70C30) is put into and in SBF solution, measures the change of its pH value,
Result is as shown in Figure 6.It can be seen that the sample pH of 45S5 and S70C30 (be and report product) is initial
168h all raises, and the pH value of PSC sample (the regenerative medicine material of the present invention) be during this period of time always maintained at constant (～
7.4, physiological ph)), as shown in Figure 6.Shown by early-stage Study, pH value raises the growth being unfavorable for cell, generally for
The cell compatibility test of 45S5 and S70C30 sample, is both needed to for sample to put into immersion 24h in PBS, removes sample
Some ions on product surface, to prevent it from killing cell.And PSC sample is changed due to its stable pH value, before typically not needing
Process, directly can carry out cell compatibility experiment, and by above test result indicate that PSC has good cytocompatibility
Property, be conducive to adhesion, propagation and the differentiation of cell.These results show that PSC is sterilized, after sterilizing, may be directly applied to internal.
Regesi regenerative medicine material piece is put into (5/50ml) in deionized water and carries out degradation experiment, at each interval
Time point replaces deionized water therein completely, takes out 5 samples, sucks the moisture on its surface with paper, put into vacuum desiccator
Middle drying, weighs, averages, result is as shown in Figure 7.Result shows：Material starts to degrade in 6d, and 9d degraded is accelerated, 70 days
Degraded can reach original 40%, and degradation rate slows down.
Regesi regenerative medicine material carries out Degrading experiment in SBF solution, with the release of material intermediate ion, in material
Surface forms HA.Start January can be degraded to original～80%, but after January, material surface is completely covered into HA, leads to
Its weight change is little, so the degraded of Regesi regenerative medicine material with the degradation rate under its in vivo metabolism should be
Accurate.At present its degraded of the 45S5 bio-vitric of report, mainly by the investigation that implants, degradable about needs 1-2.
The preclinical study that Regesi regenerative medicine materials application is repaired in backbone and segmental defects
1st, materialogy
RegeSi bioactivity glass is soaked in simulated body fluid, detects that its pH value changes；Biomechanics experiment detects
Its maximum incompressible intensity in vitro；The microstructure of electron microscope observation material, surface contact angle, by material surface spraying plating gold
Film, the surface topography of scanning material, microcellular structure.
2nd, cytology
It is separately added into RegeSi bioactivity glass as experimental group in osteoblasts cultivation liquid, choose Gsk material and make
For control group, detect this material to Gegenbaur's cell NTx, BGP, alkaline phosphatase gene expression using real-time quantitative PCR
Impact, to inquire into the mechanism that this material promotes osteoblastic proliferation further；Utilize the extraction of above two material simultaneously
Liquid cultured osteoblast-like cells in vitro, mtt assay measures cell growth curve, calculates propagation degree RGR=(experiment relatively by 6 grades of toxicity grading methods
Group/control group) × 100%, and carry out toxicity grading；Osteoblast cultured in vitro, is then seeded to above two material respectively
On, measure cell adherence rate and cell adhesion forces, adhesion rate=adherent cell number/total cell number × 100%, sucked with micro pipette
Method measurement system measures the adhesion of cell, and carries out scanning electron microscopic observation；Carry out cell to test with Material cladding, take respectively
The material of 1.0cm × 1.0cm × 0.5cm size is placed in culture plate, and cell suspension inoculation is carried out compound training in material surface
Support, under inverted phase contrast microscope, observation of cell is in the growing state of material surface.
3rd, zoopery
1) from male sheep 60, average weight 75kg, it is divided into 3 groups, every group 20.In the descending waist of general anesthesia aseptic condition
Zhui Qian road waist 2 Vertebrae resection, makes spinal segments Cranial defect model；Make ulna stage casing 4.5cm bone simultaneously and periosteum lacks
Damage model, cylindric RegeSi bioactivity glass, Gsk material, PMMA are implanted the gap after vertebral resection and ulna respectively
At defect, three kinds of repair materials are fixed at upper hypocentrum and the ulna bone defect healing of adjacent segment with titanium plate respectively.?
Knitting and defect repair situation are observed in postoperative 1st, 6,12 weeks row ulnas and l spine ap ＆ lat x-ray inspection.Put to death 3 respectively simultaneously
5 animals of individual observation group, operation removes titanium plate, takes out adjacent ulna at the adjacent vertebral including material and defect, does
Hereinafter study：A. make section, new bone growth and the material degradation situation at position filled by micro- sem observation material；B. given birth to
The incompressible and tractive intensity of material resources test specimen；C. sample is placed in Micro-CT system and carries out three-dimensional reconstruction observation, adopt
With freshman bone tissue's content of mineral substances (TMC), diaphysis fraction (BVF) at Microview ABA software quantitative analysis bone grafting；d.
It is combined the degraded surplus material showing in each sample bone grafting region with the method for Overlay superposition with different colors with newly
Raw bone.In postoperative 24th week by remaining 5 animals, take out, in general anesthesia aseptic condition menisectomy, the titanium plate that centrum and ulna are fixed,
Sew up a wound, the motion of clinical follow sheep four limbs and locomotor activity, put to death animal within postoperative 32 weeks, take out the centrum after repairing and
Ulna sample does corresponding biomethanics detection and histologic analysis.
2) 80 new zealand white rabbits are divided into castration group and sham-operation group, castration group 60, sham-operation group 20, pass through
Bilateral ovaries castration method sets up rabbit osteoporosis model.Castration group is divided into Regei group, PMMA group, blank control group, every group 20
Only, simulate vertebroplasty, inject injectable RegeSi bioactivity glass in Regei group rabbit L1, L2 centrum respectively,
PMMA group rabbit L1, L2 centrum injects PMMA, all put to death 5 rabbits in the postoperative 1st, 6,12,24 weeks for every group, takes out corresponding vertebra
Body, using histology, MicroCT analysis, the new bone growth at microscope filling position and material degradation situation, using Biological Strength
Learn experimental evaluation Regei bioactivity glass compression strength, anti-tractive intensity.
By above-mentioned experiment it was demonstrated that the Regei material of the present invention is compared with Gsk material group, PMMA group, blank control group,
There is (referring to Fig. 8 etc.) such as excellent compression strength, anti-tractive intensity and degraded situations.
The property research of existing bioactivity glass
Using 45S powdered samples as test object.
Experimentation：
1) 45S autoclave sterilization.
2) leaching liquor preparation：45S after sterilizing is immersed in the MEM culture medium of respective volume, 37oC soaks 24 hours.
Quality percent by volume is 0.1%, 1%, 10% respectively.
3) leaching liquor takes supernatant, with 1M HCl, pH is adjusted to 7.2.0.22 μm of filter sterilizing.4 DEG C of preservations.
4) three kinds of concentration leaching liquors are separately added into 10%FBS.
5) CCK-8 surveys the multiplication capacity of Hacat cell, draws absorbance-time graph.
Test result：
The 45S leaching liquor of 10% concentration is unstable, can separate out a large amount of floccules during depositing, and does not carry out follow-up test.
Find in CCK-8 test process that 1% leaching liquor adds second day complete cell death.The leaching liquor of 0.1% concentration is to cell
There is no obvious cytotoxicity, but phase cell growth is compared control group and slowed down after a test as can be seen from Figure 14.
Supplement experiment (45S is soaked in the impact to pH value in distilled water)
Experimentation：45S is soaked in distilled water according to the concentration of mass volume ratio 1%, test different time points
PH value.
Test result：
Conclusion：
Result display 45S leaching liquor constantly raises with the increase of soak time, reaches 13 in 24 hours pH value.PH significantly rises
Height leads to show very strong cytotoxicity in CCK-8 test.
Other experiments
1) 45S after autoclave sterilization is added in MEM culture medium.The percent by volume of 45S is respectively 0.1%,
1%, 10%.45S has obvious color change in addition MEM culture medium, illustrates that the pH of culture medium changes greatly.Soak
After 24h, supernatant 1M HCl is taken to adjust pH to 7.2.With the increase of 45S concentration, culture medium alkalescence is stronger, and required HCl amount is got over
Greatly.For confirming experimental result, test the change of the pH value after 45S soaks in distilled water.Test result still shows that 45S causes
PH increases considerably, and produces cytotoxicity.
2) take out ready 45S leaching liquor from 4 DEG C of refrigerators and find there are a large amount of White Flocculus 10% concentration samples.37
DEG C heating water bath half an hour does not dissolve.This concentration samples does not carry out follow-up CCK-8 test.Room temperature standing 10% concentration after two weeks
45S powder in MEM be in colloidal sol shape.Illustrate that the degradation speed of 45S powder is fast, referring to Figure 15.
3) add FBS with 0.1% and 1% concentration leaching liquor to carry out in CCK-8 test process, find the leaching liquor of 1% concentration
There is very big cytotoxicity.Complete cell death.The leaching liquor of 0.1% concentration has compared with cellule toxicity.
Industrial applicibility
The regenerative medicine material of the present invention can be used for biological Bone Defect Repari toothpaste, organizational project regeneration, the medical material of wound repair
Material, particularly exists：The aspects such as organizational project, oral mucosa, bone renovating material, wound repair have great scientific value and meaning
Justice.Significant contribution will be made in organizational project, biological therapy field.
In the case of without departing substantially from the scope of the present invention or spirit, the specific embodiment of description of the invention can be done many
Plant and improve and change, this will be apparent to those skilled in the art.Other realities being obtained by the specification of the present invention
Mode of applying is apparent obtaining for technical personnel.Present specification and embodiment are only exemplary.
Claims (10)
1. a kind of regenerative medicine material promoting hard and soft tissue to repair, described regenerative medicine material has three-dimensional net structure, and
It is the composite being made up of inorganic matter and organic matter, wherein, described inorganic matter is 2 with the mass ratio of described organic matter:1-4:
1；
Based on the gross mass of described inorganic matter, described inorganic matter comprises 12-38%SiO2, 3-5%Na2O, 15-29%CaO, 10-
32.5%P2O5, 1-5% inositol hexaphosphate, 1-5% inositol phosphate, balance of impurity, the content of described impurity is less than
0.5%；
Based on the gross mass of described organic matter, described organic matter comprises 30-60% carboxymethyl chitosan, 30-60% hyaluronic acid
Sodium.
2. according to claim 1 promote hard and soft tissue repair regenerative medicine material, wherein, described inorganic matter with described
The mass ratio of organic matter is 3:1.
3. the regenerative medicine material promoting hard and soft tissue to repair according to claim 1 and 2, wherein, in described inorganic matter
Calcium phosphorus weight ratio be 1.50 to 1.80.
4. the regenerative medicine material promoting hard and soft tissue to repair according to claim 1 and 2, its pH value is 7.4 ± 1.
5. the regenerative medicine material that the promotion hard and soft tissue described in 1 or 2 is repaired as requested, its degradation rate in vivo is 4
Week was to 12 weeks.
6. the preparation method of the regenerative medicine material promoting hard and soft tissue reparation according to any one of claim 1 to 5, its
Comprise the following steps：
Using soybean extract as phosphorus presoma, using tetraethyl orthosilicate as silicon precursor, with selected from four water-calcium nitrate, calcium nitrate
With at least one of calcium chloride as calcium precursor, using water and/or ethanol as reaction medium, by above-mentioned each precursor and reaction
Medium is hybridly prepared into Gel Precursor sol solution, and at 300～700 DEG C, Isothermal sinter obtains inorganic matter；
Described inorganic matter is mixed with carboxymethyl chitosan, Sodium Hyaluronate, heating for dissolving.
7. method according to claim 6, the preparation method of wherein said soybean extract includes：Soybean skin pulverizing → powder
Particle acidleach, filtration → leach the liquid caustic soda neutralization → calcium precipitation molten → RH of leaching+Exchange → evaporation and concentration → soybean carries resin ion
Take liquid, wherein in soybean extract, the content of hydroxyl phosphorus is 40-60 weight %.
8. a kind of cellular growth support, the hard and soft tissue that promotes that it comprises according to any one of claim 1 to 5 is repaired again
Raw medical material.
9. the regenerative medicine material according to any one of claim 1 to 5 is in the material that preparation promotes hard and soft tissue to repair
Purposes.
10. the regenerative medicine material according to any one of claim 1 to 5 is preparing medical composition, medical treatment device, oral cavity
Purposes in nursing product, plastic surgery articles for use or cosmetics.
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